Periprosthetic infection (PI) remains a challenging complication associated with total joint replacement (TJR, arthroplasty) surgeries—particularly for revision procedures with infection rates ranging from 8-15% and recurrent infection rates up to 30% [S. Kurtz, F. Mowat, K. Ong, N. Chan, E. Lau, and M. Halpern, “Prevalence of primary and revision total hip and knee arthroplasty in the United States from 1990 through 2002,” J Bone Joint Surg Am, vol. 87, pp. 1487-97, 2005]. Traditional systemic antibiotics provide insufficient antibiotic delivery to infection sites to eliminate these implant-centered infections and strictly biomaterial device-based approaches are currently inadequate [M. P. Bostrom and D. A. Seigerman, “The clinical use of allografts, demineralized bone matrices, synthetic bone graft substitutes and osteoinductive growth factors: a survey study,” Hss J, vol. 1, pp. 9-18, 2005; K. Vasilev, J. Cook, and H. J. Griesser, “Antibacterial surfaces for biomedical devices,” Expert Rev Med Devices, vol. 6, pp. 553-67, 2009; H. Winkler, O. Janata, C. Berger, W. Wein, and A. Georgopoulos, “In vitro release of vancomycin and tobramycin from impregnated human and bovine bone grafts,” J Antimicrob Chemother, vol. 46, pp. 423-8, 2000; E. Witso, L. Persen, K. Loseth, P. Benum, and K. Bergh, “Cancellous bone as an antibiotic carrier,” Acta Orthop Scand, vol. 71, pp. 80-4, 2000; E. Witso, L. Persen, K. Loseth, and K. Bergh, “Adsorption and release of antibiotics from morselized cancellous bone. In vitro studies of 8 antibiotics,” Acta Orthop Scand, vol. 70, pp. 298-304, 1999; P. Wu and D. W. Grainger, “Drug/device combinations for local drug therapies and infection prophylaxis,” Biomaterials, vol. 27, pp. 2450-67, 2006]. Thus, treatment of PI may best be achieved through the use of a local antibiotic delivery system with effective, bone-implant integration. Local antibiotic delivery to bone often lacks control over drug release kinetics, resulting in an early burst release of drug, with subsequent sustained drug release at sub-therapeutic levels and for insufficient extended time periods. This unintentionally promotes local antibiotic resistance [M. P. Bostrom and D. A. Seigerman, “The clinical use of allografts, demineralized bone matrices, synthetic bone graft substitutes and osteoinductive growth factors: a survey study,” Hss J, vol. 1, pp. 9-18, 2005]. Improved treatment of PI must not only incorporate local, controlled release mechanisms to deliver sufficient amounts of antibiotic to mitigate bacterial infection for extended durations, but also provide a void-filling scaffold to promote rapid osseointegration and restoration of bone typically lost during TJR surgery, particularly revision procedures. Combination implanted medical devices coupling an osteoconductive synthetic and biodegradable bone void filler (BVF) to promote active host bone growth and remodeling with extended antimicrobial release in situ to reduce implant reinfection rates and improve revision TJR procedure outcomes address these unmet clinical needs.
Clinical treatment of PI is complicated by bone's limited vascular supply [see Ketonis, C., et al., Clin Orthop Relat Res. 468(8): p. 2113-21, 2010; Landersdorfer, C. B., et al., Clin Pharmacokinet, 48(2): p. 89-12, 2009 and sequestra. Sequestra present a favorable, inert environment for harboring bacteria and allowing their unmitigated persistence in the protected avascular wound space Jones, S. A., et al., Wound Repair Regen, 2004. 12(3): p. 288-94, 2004; O'May, G. A., et al., “Osteomyelitis, in Biofilm Infections”, T. Bjarnsholt (ed.), Springer Science+Business Media. p. 111-137, 2011]. In addition to their persistence in biofilm and sequestra, bacteria also evade host immune and pharmacological responses by developing antibiotic resistance through metabolic senescence in biofilms or invasion into and persistence within host osteoblasts and macrophages [K. J. Bozic, S. M. Kurtz, E. Lau, K. Ong, V. Chiu, T. P. Vail, H. E. Rubash, and D. J. Berry, “The epidemiology of revision total knee arthroplasty in the United States,” Clin Orthop Relat Res, vol. 468, pp. 45-51, 2010; Wright and Nair, J. Med. Microbiol. 300(2-3): p. 193-204, 2010]. Clinical approaches routinely use local surgical device removal, surgical debridement of the tissue bed coupled with systemic antibiotic therapies, some extending for years, to attempt to eliminate TJR infections, prior to placement of a new device. Thus, current clinical tools to address acute and chronic bone infection are invasive, costly, and frequently ineffective, further compromising the patient's overall health and recovery [A. Gaudin, G. Amador Del Valle, A. Hamel, V. Le Mabecque, A. F. Miegeville, G. Potel, J. Caillon, and C. Jacqueline, “A new experimental model of acute osteomyelitis due to methicillin-resistant Staphylococcus aureus in rabbit,” Lett Appl Microbiol, vol. 52, pp. 253-7, 2011; E. Moran, I. Byren, and B. L. Atkins, “The diagnosis and management of prosthetic joint infections,” J Antimicrob Chemother, vol. 65 Suppl 3, pp. iii45-54, 2010]. Moreover, the economic burden for surgically addressing PI with revision TJR is calculated to be 5.3-7.2 times higher than that of primary TJR operations [A. Gaudin, G. Amador Del Valle, A. Hamel, V. Le Mabecque, A. F. Miegeville, G. Potel, J. Caillon, and C. Jacqueline, “A new experimental model of acute osteomyelitis due to methicillin-resistant Staphylococcus aureus in rabbit,” Lett Appl Microbiol, vol. 52, pp. 253-7, 2011]. This amounts to $750 million in insurance and patient costs to treat spine, knee and hip infections and nearly $250 million in hospital losses yearly [P. V. Giannoudis, H. Dinopoulos, and E. Tsiridis, “Bone substitutes: an update,” Injury, vol. 36 Suppl 3, pp. S20-7, 2005]. This billion-dollar infection impact remains unaddressed with effective clinical approaches.
No clinical long-term controlled release approaches exist for locally treating bone infection. Current approaches for treatment or prevention of PI fall into two groups, often administered simultaneously. Systemic antibiotic prophylaxis is considered the current clinical standard of care; however, studies are lacking to support this approach to PI [A. Gaudin, G. Amador Del Valle, A. Hamel, V. Le Mabecque, A. F. Miegeville, G. Potel, J. Caillon, and C. Jacqueline, “A new experimental model of acute osteomyelitis due to methicillin-resistant Staphylococcus aureus in rabbit,” Lett Appl Microbiol, vol. 52, pp. 253-7, 2011; A. M. Gonzalez Della Valle, “Effective Bactericidal Activity of Tobramycin and Vancomycin Eluted from Acrylic Bone Cement,” Acta Orthop Scand, vol. 72, pp. 237-40, 2001]. While considered generally effective, problems with systemic antibiotic delivery include systemic side effects and low antibiotic concentration at bone infection sites, potentially promoting antibiotic resistance [A. Gaudin, G. Amador Del Valle, A. Hamel, V. Le Mabecque, A. F. Miegeville, G. Potel, J. Caillon, and C. Jacqueline, “A new experimental model of acute osteomyelitis due to methicillin-resistant Staphylococcus aureus in rabbit,” Lett Appl Microbiol, vol. 52, pp. 253-7, 2011; T. Miclau, L. E. Dahners, and R. W. Lindsey, “In vitro pharmacokinetics of antibiotic release from locally implantable materials,” J Orthop Res, vol. 11, pp. 627-32, 1993]. The second treatment option involves localized delivery of antibiotics directly to the site of infection. This strategy is commonly embodied by 1) surgical debridement with an antibiotic solution [P. V. Giannoudis, H. Dinopoulos, and E. Tsiridis, “Bone substitutes: an update,” Injury, vol. 36 Suppl 3, pp. S20-7, 2005], 2) application of antibiotic solutions to bone grafts by soaking them in high concentration antibiotic solutions, and 3) implantation of antibiotic-loaded bone cements (only available during revision TJR). Surgical debridement with antibiotic solutions may provide immediate protection at the surgical site but has no lasting efficacy. Simple drug adsorption to bone without a controlled release design defaults to rapid bolus drug release within the first few days [T. N. Peel, K. L. Buising, and P. F. Choong, “Diagnosis and management of prosthetic joint infection,” Curr Opin Infect Dis, vol. 25, pp. 670-6, 2012], with essentially no further release above the minimum inhibitory concentration [T. Miclau, L. E. Dahners, and R. W. Lindsey, “In vitro pharmacokinetics of antibiotic release from locally implantable materials,” J Orthop Res, vol. 11, pp. 627-32, 1993]. These off-label graft-drug preparations lack uniform fabrication, validation, and dosing, and proven efficacy and may result in the development of antibiotic resistant pathogens [T. N. Peel, K. L. Buising, and P. F. Choong, “Diagnosis and management of prosthetic joint infection,” Curr Opin Infect Dis, vol. 25, pp. 670-6, 2012]. Directly soaking bone filler materials in antibiotics is studied extensively. However, technology that endows this matrix with a legitimate, controlled release design for extended bioactive drug release has not been translated from laboratory to clinic [M. P. Bostrom and D. A. Seigerman, “The clinical use of allografts, demineralized bone matrices, synthetic bone graft substitutes and osteoinductive growth factors: a survey study,” Hss J, vol. 1, pp. 9-18, 2005; H. Winkler, O. Janata, C. Berger, W. Wein, and A. Georgopoulos, “In vitro release of vancomycin and tobramycin from impregnated human and bovine bone grafts,” J Antimicrob Chemother, vol. 46, pp. 423-8, 2000; T. N. Peel, K. L. Buising, and P. F. Choong, “Diagnosis and management of prosthetic joint infection,” Curr Opin Infect Dis, vol. 25, pp. 670-6, 2012, Y. Achermann, M. Vogt, M. Leunig, J. Wust, and A. Trampuz, “Improved diagnosis of periprosthetic joint infection by multiplex PCR of sonication fluid from removed implants,” J Clin Microbiol, vol. 48, pp. 1208-14, 2010; A. E. Brooks, B. D. Brooks, S. N. Davidoff, P. C. Hogrebe, M. A. Fisher, and D. W. Grainger, “Polymer-controlled release of tobramycin from bone graft void filler,” Drug Deliv and Transl Res, vol. 3, pp. 518-530, 2013; S. N. Davidoff, J. O. Sevy, B. D. Brooks, D. W. Grainger, and A. E. Brooks, “Evaluating Antibiotic Release Profiles As A Function Of Polymer Coating Formulation,” Biomed Sci Instrum, vol. 47, pp. 46-51, 2011; D. R. Osmon, E. F. Berbari, A. R. Berendt, D. Lew, W. Zimmerli, J. M. Steckelberg, N. Rao, A. Hanssen, and W. R. Wilson, “Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America,” Clin Infect Dis, vol. 56, pp. e1-e25, 2013]. Routine use of antibiotic-loaded bone cement (ALBC) is a classic example of local antibiotic delivery controlled by a glassy, non-swelling, non-biodegradable glassy polymer foreign body, presenting its own challenges.
To address the complete spectrum of implant infection risk and virulence factors, an active antimicrobial implant should maintain antibiotic concentrations at bactericidal levels for greater than 6 weeks, eliminating latent persister (senescent, quiescent or “sleeper”) bacteria that due to their inactive metabolic states are not susceptible to most antibiotic activities [B. D. Brooks, K. D. Sinclair, S. N. Davidoff, S. Lawson, A. G. Williams, B. Coats, D. W. Grainger, and A. E. Brooks, “Molded polymer-coated composite bone void filler improves tobramycin controlled release kinetics,” J Biomed Mater Res, vol. in press, 2013; A. E. Brooks, B. D. Brooks, S. N. Davidoff, B. P. Call, P. C. Hogrebe, M. Fisher, and D. W. Grainger, “Tailored Polymer-Controlled Release of Tobramycin from Allograft Bone Void Filler,” Pharmaceutics and Pharmaceutical Chemistry, Pathology, and Bioengineering. Salt Lake City: University of Utah, 2010; A. E. Brooks, B. D. Brooks, S. N. Davidoff, P. C. Hogrebe, M. A. Fisher, and D. W. Grainger, “Polymer-controlled release of tobramycin from bone graft void filler,” Drug Deliv and Transl Res, vol. 3, pp. 518-530, 2013] and reducing opportunities for acquired antibiotic resistance. Current implantable clinical antimicrobial products for TJR mitigation do not use degradable polymers to control antibiotic release and therefore release antibiotic for durations of a few days to maximum 3-4 weeks. Antibiotic-loaded bone cement, a standard of care for revision TJR procedures, exhibits a high initial burst release of antibiotics (up to 80% of total drug load within a few days), is a non-degradable foreign body in bone and tissue, and continues to elute antibiotic at sub-therapeutic concentrations [M. P. Bostrom and D. A. Seigerman, “The clinical use of allografts, demineralized bone matrices, synthetic bone graft substitutes and osteoinductive growth factors: a survey study,” Hss J, vol. 1, pp. 9-18, 2005; H. Winkler, O. Janata, C. Berger, W. Wein, and A. Georgopoulos, “In vitro release of vancomycin and tobramycin from impregnated human and bovine bone grafts,” J Antimicrob Chemother, vol. 46, pp. 423-8, 2000; W. A. Jiranek, A. D. Hanssen, and A. S. Greenwald, “Antibiotic-loaded bone cement for infection prophylaxis in total joint replacement,” J Bone Joint Surg Am, vol. 88, pp. 2487-500, 2006; A. C. McLaren, “Alternative materials to acrylic bone cement for delivery of depot antibiotics in orthopaedic infections,” Clin Orthop Relat Res, pp. 101-6, 2004] for weeks to months, or even years, beyond the intended antibiotic therapeutic window. Prolonged elution of antibiotic below the therapeutic level may inadvertently promote antibiotic resistance [D. Campoccia, L. Montanaro, P. Speziale, and C. R. Arciola, “Antibiotic-loaded biomaterials and the risks for the spread of antibiotic resistance following their prophylactic and therapeutic clinical use,” Biomaterials, vol. 31, pp. 6363-77, 2010]. Unlike ALBC, a degradable and osteoconductive implanted matrix—allowing restoration of surgical site bone volumes—that also delivers antibiotics to infection sites locally at controlled, efficacious levels and extended durations beyond 6-8 weeks is not currently practiced. Some current art describes extended antibiotic release from largely degradable polymer implant matrices to bone infections; other art describes antibiotic delivery from largely inorganic implantable matrices.